The present invention relates to the transdermal delivery of the active enantiomer or the racemic form of ketorolac from a patch that can deliver a therapeutically effective dose of the drug through the skin of a patient in need of such treatment for an extended period of time of at least 12 hours or more.
Ketorolac is a non-steroidal anti-inflammatory agent with potent analgesic properties. The drug is currently administered as the racemic mixture orally or by injection and is commercially available in forms suited for such modes of delivery. Ketorolac tromethamine salt in sterile water for intramuscular and intravenous administration is available at concentrations ranging from 1.5% (15 mg in 1 ml) to 3% (60 mg in 2 mls). Typically, when injected, a bolus dose of 30 to 60 mg is first given followed by subsequent injections of half the loading dose (15 to 30 mg) every 6 to 8 hours. The total daily doses of the drug as such is in the range of 60-120 mg. Delivered at these levels, the drug is extremely effective. However, the need for repeated injections due to the relatively rapid metabolism of the drug makes this mode of delivery inconvenient in certain situations.
A far more convenient and acceptable form of delivery is simple oral delivery 2 to 3 times per day. However, oral administration of ketorolac can be quite irritating to the gastrointestinal tract. Thus, for oral use, the FDA has approved only low-dosage tablets containing only 10 mg of ketorolac tromethamine salt. Of course patients can take more than one tablet, but in general it is normally not safely possible to maintain the same highly effective blood levels obtained with the injectable form when the drug is given orally.
Thus there is an interest in developing alternative modes of delivering ketorolac which do not have the gastrointestinal side effects produced by oral formulations but which are more convenient than injection methods. Nasal formulations of ketorolac are described in application U.S. Ser. No. 875,700, filed Apr. 29, 1992. In co-pending application U.S. Ser. No. 07/973,801 filed Nov. 9, 1992, now abandoned, the transdermal delivery of the active enantiomer of ketorolac is described.
The use of transdermal patches for drug delivery is particularly beneficial when it is desired to maintain a constant blood level of drug in the patient for extended periods of time. There is an added benefit in that oftentimes, the required dose of a drug when delivered by a 24 hour transdermal patch can be one half or less that of the dose delivered by a single once a day intravenous or oral dose. This is particularly true if the drug has a high clearance value. With conventional drug delivery methods, if a drug has a high clearance value it is necessary to administer a large dose of the drug to extend the time it takes the blood drug levels to fall below the therapeutically effective level. But with transdermal delivery, the dose of a drug with a high clearance value can be lower since the drug is controlled released, and does not have to be administered at levels much greater than the therapeutically effective level.
The concept of clearance is described in detail in Rowland & Tozer's, Clinical Pharmacokinetics: Concepts and Applications, (2nd Ed. 1989) [hereinafter Rowland & Tozer]. Briefly, clearance does not indicate how much drug is being removed from the system but, rather, the volume of biological fluid such as blood or plasma that would have to be completely freed of drug to account for the elimination. Clearance is expressed as a volume per unit of time. Clearance by means of various organs of elimination is additive. Elimination of drug may occur as a result of processes that occur in the kidney, liver, and other organs. When the respective clearance by each organ is added together, they equal total systemic clearance.
The half-life of a drug is the amount of time it takes the total level of drug in a body to decrease by 50%. Clearance is related to the half-life of a drug by Equation 1: ##EQU1## The relationship between the conventional dose of a drug and the dose of drug delivered transdermally can be calculated if the half-life of the drug is known. This procedure is described on pages 5-10 of Baker, R. W., Controlled Release of Biologically Active Agents, John Wiley and Sons, New York, (1987) [hereinafter Baker]. Using this procedure, the data shown in Table I and FIG. 1 has been calculated.
Table I shows that the ratio of dose required for the transdermal delivery of a drug compared to the dose required for conventional drug delivery decreases as the half-life of the drug decreases. Thus, if the half-life of the drug is 24 hours, then a transdermal patch delivering drug to the body at a relatively constant rate should only have to deliver 84.5% of the dose of a conventional instant dose form of the drug delivered once every 24 hours. In this case, the advantage offered by controlled transdermal delivery is relatively small, only a 15.5% reduction in dose. However, if the half-life of the drug is 4 hours, the approximate half-life of ketorolac, then the advantage offered by constant delivery is much greater compared to conventional delivery given once every 24 hours, namely a reduction in dose of almost 75%. Even if an injectable dose is given every 8 hours, the reduction in dose obtained when a transdermal patch is used is still substantial, being on the order of 40 to 50%.
TABLE I ______________________________________ Ratio of dose required of controlled release form Drug Half-life compared to conventional form (in hours) (for a 24-hour device) ______________________________________ 24 0.845 12 0.595 6 0.350 4 0.250 3 0.205 ______________________________________
Thus it follows that if the total amount of ketorolac delivered by regular injections three times a day to control pain is approximately 60-120 mg/day, then a 30-60 mg/day dose delivered transdermally would produce approximately the same benefit without the problems of overdosing and underdosing associated with injectable delivery. This type of calculation has lead to interest in delivering ketorolac transdermally. For example, transdermal delivery of ketorolac from nearly saturated solutions in various enhancer combinations has been studied by others (D. Yu et al, Pharm. Res. 5(7): 457-462, (1988)). In another study, a 2% ketorolac topical gel was studied (R. Greenwald, Drugs of Today, 29(1): p.52, (1992)). The patients applied 3 g of the gel three times per day without occlusion. Serum concentrations of approximately 0.17-0.18 .mu.g/ml were attained, significantly below the generally accepted target level for good analgesia with ketorolac of 0.3 to 5.0 .mu.g/ml.
These dissatisfying results are not surprising. It is well known in the art of transdermal drug delivery that it is very difficult to deliver drugs at a rate of greater than 10-20 .mu.g/cm.sup.2 .multidot.hr. Of the 9 drugs delivered by approved commercial transdermal formulations only two, nicotine and nitroglycerine, both very permeable liquids, deliver drug at this rate. Most of the other formulations deliver the drugs at a much lower rate. It has been proposed that the permeability of skin to a given drug can be correlated with the drug's melting point according to the relationship set forth in FIG. 2 (Baker, supra). Based on this, the expected flux of ketorolac with a melting point of 160.degree. C. would be 0.06 .mu.g/cm.sup.2 .multidot.hr. The expected flux of ketorolac tromethamine, which has melting point similar to that of the free acid, would be about the same.
It follows that if the estimated transdermal dose of 30-60 mg/day of ketorolac is to be delivered by a transdermal device, the area of the patch required would be impossibly large, on the order of 2-4 m.sup.2. Of course, skin permeation enhancers could be used to increase the delivery, but if conventional sized patches of the order of 30 cm.sup.2 or less are to be used, skin permeation rates from the patch of the order of 42-84 .mu.g/cm.sup.2 .multidot.hr would be required--a very considerable degree of enhancement.
Patch design is governed by several factors: permeability of drug to the skin, dose of drug required, enhancers used to deliver drug, and the flux rate of drug and enhancer required to achieve a therapeutic effect. Accordingly, there is much literature on the design of transdermal patches, with variations on a particular design being influenced by the above factors. Liquid reservoir patches of various designs are well known to researchers in the field of transdermal drug delivery. For example, U.S. Pat. No. 4,460,372 ('372) discloses a transdermal patch having, in order from skin-distal side of patch to skin-facing side of patch, a backing layer, an enhancer reservoir layer containing a solvent type enhancer such as ethanol, a diffusion membrane layer, and a drug reservoir-contact adhesive layer. In this patent, a rate-controlling membrane separates an enhancer reservoir from the drug depot rather than having the enhancer and drug within the same compartment. The premise is that the drug delivered does not need the rate-controlling effect of the diffusion membrane layer, whereas the enhancer does. Without the diffusion membrane layer, the flux of the enhancer would be too high. However, if the drug were to pass through the diffusion membrane layer, its flux would be too low to achieve a therapeutic effect.
In U.S. Pat. No. 4,379,454, a patch somewhat similar to the '372 patch is described. The difference with this patch is that both the drug and the solvent enhancer are contained in the reservoir layer and are separated from the skin by a microporous membrane. The membrane is quite permeable to the drug which is able to permeate the membrane at a rate higher than the skin's ability to absorb the drug. However, the membrane is relatively less permeable to the enhancer. As a result, the enhancer permeates the membrane, and subsequently the skin, at a rate less than the skin's ability to absorb the enhancer. The membrane is thus a rate controlling barrier for the enhancer. When this type of patch is used to deliver drug, the rate of absorption of the drug can be controlled mostly by the permeability of the membrane to the enhancer. If the membrane is relatively impermeable to the enhancer, the rate of delivery of enhancer to the skin will be low and the enhancement effect achieved will also be low. This will result in a low drug absorption rate. Correspondingly if the permeability of the membrane to enhancer is high, the rate of delivery of enhancer to the skin will also be high as well as the resulting enhancement effect achieved. This will result in a high drug absorption rate. The difficulty with these types of devices is that they require precise control of the enhancers permeability through the membrane to achieve good control of drug absorption. In practice, this level of control is difficult to achieve.
U.S. Pat. No. 4,031,894 describes another type of transdermal patch having an impermeable backing layer, a layer of drug gelled in mineral oil, a microporous membrane, and a contact adhesive layer containing drug. The drug in the contact adhesive layer is the "pulse dosage" which rapidly permeates through the patient's skin. Thereafter the delivery rate of the drug is controlled by the microporous membrane.
European patent application 0 413 487 A1 discloses a transdermal patch for the delivery of dexmedetomidine. It comprises (from skin distal to skin-facing side) a backing layer, an adhesive layer, a porous intermediate layer, a drug/contact adhesive layer, and a release liner. The porous intermediate layer functions as structural reinforcement and can be made of a non rate-controlling, nonwoven fabric such as polyester. Upon fabrication, the anchor adhesive and contact adhesive migrate into the intermediate layer.
None of the above references disclose a transdermal patch design that is useful in delivering therapeutic amounts of ketorolac. Accordingly, it is an object of this invention to provide a transdermal patch that can deliver ketorolac at a rate that attains a therapeutic level.
Another object of the present invention is to provide a ketorolac transdermal patch that is less than 30 cm.sup.2 in active surface area.
It is a further object of the invention to provide a transdermal ketorolac patch that avoids or minimizes skin irritation.
Another object of the invention is to provide a ketorolac transdermal patch that is effective in providing analgesia for periods of 12 hours or more.
These and other objects and features of the invention will be apparent to those skilled in the art from the following detailed description and appended claims when taken in conjunction with the figures.